1. Field of the Invention
The present invention relates to a novel process for preparing cephalosporin compounds useful as antibiotics. More specifically, the present invention relates to a novel process for preparing cephem derivatives represented by the following formula (I) having 2-[aminothia(dia)zolyl]-2-methoxyiminoacetamido group on the 7-position of cephem nucleus, characterized in that a reactive thiophosphate of thia(dia)zole acetic acid having the following formula (II) (hereinafter referred as to "the reactive organic acid derivative") is acylated with a 7-ACA (7-aminocephalosporanic acid) derivative: ##STR4## in which R.sup.1 represents a carboxy group or a protected carboxy group which can form the salt of --COO.sup.- M.sup.+ with an alkali metal ion (M.sup.+) such as sodium, or may represent --COO.sup.- when R.sup.2 has a substituent having positive electric charge such as pyridinium, pyrimidinium or thiazolium,
R.sup.2 represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which can be substituted with appropriate substituents, PA1 R.sup.3 represents hydrogen or an amino-protecting group, PA1 R.sup.4 represents C.sub.1 -C.sub.4 alkyl or phenyl, or together with the oxygen or phosphorus atom to which it is attached may form a 5- or 6-membered heterocyclic ring, and PA1 Q represents N or CH. PA1 R.sup.2 represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which can be substituted with appropriate substituents, PA1 R.sup.3 represents hydrogen or an amino-protecting group, PA1 R.sup.4 represents C.sub.1 -C.sub.4 alkyl or phenyl, or together with the oxygen or phosphorus atom to which it is attached may form a 5- or 6-membered heterocyclic ring, and PA1 Q represents N or CH. PA1 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamide-3-cephem-4-carboxylic acid (Cefotaxime); 7-[[2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro- 6-hydroxy -2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl]-3-cephem-4-carboxylic acid (Ceftriaxone); 7-[[.alpha.-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino]acetamido]-3-[(1-meth yl-1H-tetrazol-5-yl)-thiomethyl]-cephem-4-carboxylic acid (Cefmenoxime); 7-[2-methoxyimino-2-(2-amino -1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (Ceftizoxime); 7-[[2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino]acetamido]-3-(2,3-dicyclope ntenopyridiniummethyl)-3-cephera-4-carboxylate (Cefpirome); 7-[[2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(1-methylpyrrolidi ummethyl)-3-cephem-4-carboxylate (Cefepime); 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(4,6-diamino-1 -methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-1,2,4-thiazol-3-yl)-2-methoxyimino]acetamido]-3-(4,6-di amino-1-methylpyrimidinium-2-yl)thiomethyl -3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino]acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamido]-3-(1,4,6-triaminopyrimidinium -2-yl) thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamido]-3-(4,6-diamino-1,5-dimethylpyrimidinium-2-yl)th iomethyl -3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino -4-thiazolyl) -2-methoxyimino]acetamido]-3-(2,6-diamino-1-methylpyrimidinium-4-yl)thiome thyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3- (2,6-diamino -1-ethylpyrimidinium-4-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamido]-3-(2,6-diamino-3-ethylpyrimidinium-4-yl) thiomethyl-3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl)-2-methoxyimino]-acetamido]-3-(2,6-diamino-3-methy lpyrimidinium-4-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(4,5,6-triamino-1-met hylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(4-amino-1-methylpyri midinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(4-amino-1-met hylpyrimidinium-2-yl)-thiomethyl -3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(4-amino-1-carboxymet hylpyrimidinium-2-yl) -thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamido]-3-(4-amino-1-aminopyrimidinium-2-yl)-thiomethyl -3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamido]-3-(1,4,5-triaminopyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl) -2-methoxyimino]acetamido]-3-(4-amino-1-meth-yl-6-(N,N-dimethyl) aminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acet-amido]-3-(1, 4,5,6-tetraaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(1,4-diamino-5 -methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z) -2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(1,4-diamino-5-ethylp yrimidinium-2-yl)thiomethyl-3-cephem -4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(1,4-diamino-6 -(N-methyl)aminopyrimidinium-2-yl) -thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl) -2-methox-yimino]acetamido]-3-(1,4-diamino-5-methyl-6-(N-methyl) aminopyrim-idinium-2-yl)thiomethyl-3-cephem-4-carbox-ylate; 7- [[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(3,4-diamino-3,5 ,6,7-tetrahydrocyclopentapyrimidinium-2-yl)thiomethyl -3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(2-amino-1-met hyl-1,5,6,7-tetrahydrocyclopentapyrimidinium -4-yl)thiomethyl-3-cephem-4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino]acetamido]-3-(1,2-diamino -1,5,6,7-tetrahydrocyclopentapyrimidinium-4-yl) thiomethyl-3-cephem -4-carboxylate; 7-[[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino acetamido]-3-(7-amino-1-methyl[1,2,49 triazolo[1,5-c]pyrimidinium -5-yl)thiomethyl-3-cephem-4-carboxylate; or 7-[[(Z)-2-(2-amino -4-thiazolyl)-2-methoxyimino]acetamido]-3-(1-methyl[1,3]imidazo [1,2-c]pyrimidinium-5-yl)thiomethyl-3-cephem-4-carboxylate.
2. Background Art
In general, numerous methods for preparing .beta.-lactam antibiotics have been disclosed in prior publications and patent specifications. Such prior methods prepare the .beta.-lactam antibiotic compounds commonly starting from an organic acid represented by the following formula (A) which is converted into a reactive derivative thereof and then subjected to the acylation reaction with an amino group of the .beta.-lactam nucleus: ##STR5## wherein R.sup.3 and Q are defined as previously described.
The reactive derivatives which have been known from the above prior methods include an acid chloride, a reactive ester, a reactive amide, a mixed acid anhydride and the like. However, the reactive derivative in the form of an acid chloride or a mixed acid anhydride is prepared under a stringent reaction condition and further is unstable so that it might be used in situ for the acylation reaction without isolation. This may be the major reason for the formation of by-products. In addition, the reactive ester and the reactive amide have also disadvantages in that they are prepared in a low yield, their reactivity is very low and so requires long reaction time, and further the reaction by-products, for example, a hydroxy derivative such as 1-hydroxybenzotriazole and a thiol derivative such as 2-mercaptobenzothiazole can be hardly removed.
Thus, the present inventors have continuously studied to find out a method which can solve the problems involved in the known reactive derivatives as previously described and succeeded in preparing a novel reactive derivative having a suitable reactivity and stability in a high yield and a high purity from the organic acid of formula (A) and a chlorothiophosphate derivative by means of a convenient method (see U.S. patent application Ser. No. 08/223,756, filed Apr. 6, 1995). Further, now we have disclosed that the cephem derivative of formula (I) useful as an antibiotic can be more economically prepared starting from said reactive organic acid derivative and then completed the present invention.
Therefore, it is an object of the present invention to provide a novel process for preparing cephem derivatives represented by the formula (I) as defined above.
It is a further object of the present invention to provide a novel process for preparing cephem derivatives, as defined above, starting from a reactive thiophosphate derivative of thia(dia)zole acetic acid having the formula (II) as defined above.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention, in addition to the scope of the invention defined by the claims.